Biologically absorbable coating for implantable devices based on copolymers having ester bonds and methods of fabricating the same

ABSTRACT

Coatings for an implantable medical device and a method of fabricating thereof are disclosed, and the coatings comprise biologically absorbable poly(ester amides).

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. application Ser.No. 10/805,036 filed on Mar. 16, 2004, the teaching of which isincorporated by reference in its entirety herein.

BACKGROUND

1. Field of the Invention

This invention is directed to coatings for drug delivery devices, suchas drug eluting vascular stents, and methods for producing the same.

2. Description of the State of the Art

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure fortreating heart disease. A catheter assembly having a balloon portion isintroduced percutaneously into the cardiovascular system of a patientvia the brachial or femoral artery. The catheter assembly is advancedthrough the coronary vasculature until the balloon portion is positionedacross the occlusive lesion. Once in position across the lesion, theballoon is inflated to a predetermined size to radially compress againstthe atherosclerotic plaque of the lesion to remodel the lumen wall. Theballoon is then deflated to a smaller profile to allow the catheter tobe withdrawn from the patient's vasculature.

A problem associated with the above procedure includes formation ofintimal flaps or torn arterial linings which can collapse and occludethe conduit after the balloon is deflated. Moreover, thrombosis andrestenosis of the artery may develop over several months after theprocedure, which may require another angioplasty procedure or a surgicalby-pass operation. To reduce the partial or total occlusion of theartery by the collapse of arterial lining and to reduce the chance ofthe development of thrombosis and restenosis, a stent is implanted inthe lumen to maintain the vascular patency.

Stents are used not only as a mechanical intervention but also as avehicle for providing biological therapy. As a mechanical intervention,stents act as scaffoldings, functioning to physically hold open and, ifdesired, to expand the wall of the passageway. Typically, stents arecapable of being compressed, so that they can be inserted through smallvessels via catheters, and then expanded to a larger diameter once theyare at the desired location. Examples in patent literature disclosingstents which have been applied in PTCA procedures include stentsillustrated in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No.4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062 issued toWiktor.

Biological therapy can be achieved by medicating the stents. Medicatedstents provide for the local administration of a therapeutic substanceat the diseased site. In order to provide an efficacious concentrationto the treated site, systemic administration of such medication oftenproduces adverse or toxic side effects for the patient. Local deliveryis a preferred method of treatment in that smaller total levels ofmedication are administered in comparison to systemic dosages, but areconcentrated at a specific site. Local delivery thus produces fewer sideeffects and achieves more favorable results. One proposed method formedicating stents involves the use of a polymeric carrier coated ontothe surface of a stent. A solution which includes a solvent, a polymerdissolved in the solvent, and a therapeutic substance dispersed in theblend is applied to the stent. The solvent is allowed to evaporate,leaving on the stent surface a coating of the polymer and thetherapeutic substance impregnated in the polymer.

One polymer that can be used for making stent coatings for local drugdelivery can be selected from a group of poly(ester amides) described inU.S. Pat. No. 6,503,538 to Chu et al. However, some mechanicalproperties, such as hardness of the poly(ester amides) taught by Chu etal. may be insufficiently good for stent applications. Accordingly,there is a need to have poly(ester amides) with better properties toallow the poly(ester amides) to be used to make stent coatings for localdrug delivery.

SUMMARY

According to one aspect of the present invention, a medical article isprovided, the article comprises an implantable substrate having acoating, the coating includes a polymeric product of a reaction betweena first reagent, a second reagent, and a third reagent, wherein: (a) thefirst reagent can be one of the compounds having formulae (1), (2), (3),and (4);

(b) the second reagent can be one of the compounds having formulae (5),(6), (7), and (8);

and, (c) the third reagent can be a dicarboxylic acid having the formula(9):

In formulae (1)-(9), R₁ can be hydrogen, methyl, iso-propyl, sec-butyl;iso-butyl, or benzyl group; R₂ can be methylene, methylmethylene,n-propylene, iso-propylene, ethylmethylene, n-butylene, iso-butylene,sec-butylene, or n-amylene group; R₃ can be a straight chained orbranched aliphatic alkylene group C_(n)H_(2n), wherein n is an integerbetween 2 and 12; R₄ can be a moiety derived from a compound selectedfrom a group consisting of poly(ethylene glycol), polypropylene glycol),random poly(ethylene glycol-co-propylene glycol), poly(ethyleneglycol)-block-polypropylene glycol), hyaluronic acid,poly(2-hydroxyethyl methacrylate), poly(3-hydroxypropylmethacrylamide),poly(styrene sulfonate), poly(vinyl pyrrolidone), and cellulosics; X canbe a straight chained or branched aliphatic alkylene group C_(n)H_(2n),wherein n is an integer between 2 and 12; and Y can be a straightchained or branched aliphatic alkylene group C_(n)H_(2n), wherein n is1, 2, or 5.

According to another aspect of the present invention, a medical articleis provided. The article comprises an implantable substrate having acoating, and the coating includes a copolymer having a general formula(10) or (11):

-[M-P]_(m)-[M-Q]_(n)-  (10)

-[M₁-P]_(p)-  (11)

wherein, M can be a moiety represented by the structure having theformula (12);

P can be one of the moieties having the formulae (13), (14), (15), and(16);

Q can be one of the moieties having the formulae (17), (18), and (19);

and M₁ can be a moiety represented by the formula (20);

In formulae (10)-(20), R₁ can be hydrogen, methyl, iso-propyl,sec-butyl; iso-butyl, or benzyl group; R₂ can be methylene,methylmethylene, n-propylene, iso-propylene, ethylmethylene, n-butylene,iso-butylene, sec-butylene, or n-amylene group; R₃ can be a straightchained or branched aliphatic alkylene group C_(n)H_(2n), wherein n isan integer between 2 and 12; X can be a straight chained or branchedaliphatic alkylene group C_(n)H_(2n), wherein n is an integer between 2and 12; Y can be a straight chained or branched aliphatic alkylene groupC_(n)H_(2n), wherein n is 1, 2, or 5; Z can be a moiety derived from acompound selected from a group consisting of poly(ethylene glycol),poly(propylene glycol), random poly(ethylene glycol-co-propyleneglycol), poly(ethylene glycol)-block-poly(propylene glycol), hyaluronicacid, poly(2-hydroxyethyl methacrylate),poly(3-hydroxypropylmethacrylamide), poly(styrene sulfonate), poly(vinylpyrrolidone), and cellulosics; and m, n, and p can be integers where thevalue of m is between 5 and 1,800, the value of n is between 1 and 800and the value of p is between 4 and 1,500.

According to yet another aspect of the current invention, a method forfabricating a medical article is provided, the method includessynthesizing a copolymer and forming a coating based on the copolymer onat least a portion of an implantable substrate, the synthesizing of thecopolymer including reacting a first reagent with a second reagent andwith a third reagent, wherein: (a) the first reagent can be one of thecompounds having formulae (1), (2), (3), and (4); (b) the second reagentcan be one of the compounds having formulae (5), (6), (7), and (8); and(c) the third reagent is a dicarboxylic acid having the formula (9),where the formulae (1)-(9) are provided above.

According to yet another aspect of the current invention, a method forfabricating a medical article is provided, the method includingsynthesizing a copolymer and forming a coating based on the copolymer onat least a portion of an implantable substrate, wherein the copolymerhas a general formula (10) or (11), where the formulae (10) and (11) areprovided above.

DETAILED DESCRIPTION 1. Terms and Definitions

The following definitions apply:

The term “biologically absorbable” coatings and/or polymers is definedas coatings and/or polymers that are capable of being completelydegraded and/or eroded when exposed to bodily fluids such as blood andare gradually resorbed, absorbed and/or eliminated by the body. Theprocesses of breaking down and eventual absorption and elimination ofthe coating and/or polymer can be caused, for example, by hydrolysis,metabolic processes, bulk or surface erosion, and the like.

Whenever the reference is made to “biologically absorbable” stentcoatings and/or polymers forming such stent coatings, it is understoodthat after the process of degradation, erosion, absorption, and/orresorption has been completed, no coating, in excess of possiblyinsignificant trace amount, will remain on the stent. In other words,stent coatings and/or polymers forming such stent coatings areconsidered “biologically absorbable” if the coatings and/or polymers aresubstantially broken down by the in vivo environment, or by the in vitroenvironment, such as one having physical, chemical, and/or biologicalcharacteristics substantially similar to those of the in vivoenvironment. An amount of time needed to break down the coatings and/orpolymers can be between about 1 day and several years, or between about1 day and about 24 months; alternatively, between about 2 months andabout 18 months; alternatively, between about 3 month and about 12months.

For purposes of the present invention, “substantially broken down” meansthat a substantial reduction of the molecular weight of a polymer occursas a result of the exposure of the polymer to the in vivo environment orto a simulated in vivo environment. The simulated in vivo environmentcan be the in vitro environment having physical, chemical, and/orbiological characteristics that are identical or substantially similarto those of the in vivo environment. Standard analytical techniquesnormally used by those having ordinary skill in the art can be used tomonitor the change of the molecular weight of the polymer. Oneanalytical technique that can be used includes immersing the polymer ina simulated in vivo environment and measuring the loss of the molecularweight of the polymer over time. A number of methods can be used formeasuring the molecular weight, for example, gel permeationchromatography (GPC). In some embodiments, if the polymer has lost morethan about 10% of its original molecular weight over a 3-month period,then it can be classified as biodegradable.

The term “poly(ester amide)” or “PEA” is defined as a polymer havingboth at least one ester bond (I) and at least one amide bond (II):

2. Embodiments of the Invention

A coating for an implantable medical device, such as a stent, accordingto embodiments of the present invention, can be a multi-layer structurethat can include the following three layers:

(a) a drug-polymer layer (also referred to as “reservoir” or “reservoirlayer”), comprising a polymer and a drug, or alternatively a polymerfree drug layer;

(b) an optional primer layer; and/or

(c) an optional topcoat layer.

Each layer of the stent coating can be formed on the stent by dissolvinga polymer or a blend of polymers in a solvent, or a mixture of solvents,and applying the resulting polymer solution on the stent by spraying orimmersing the stent in the solution. After the solution has been appliedonto the stent, the coating is dried by allowing the solvent toevaporate. The process of drying can be accelerated if the drying isconducted at an elevated temperature.

To incorporate a drug into the reservoir layer, the drug can be combinedwith the polymer solution that is applied onto the stent as describedabove. Alternatively, to fabricate a polymer-free drug layer, the drugcan be dissolved in a suitable solvent or mixture of solvents, and theresulting drug solution can be applied on the stent by spraying orimmersing the stent in the drug solution.

Instead of introducing the drug as a solution, the drug can beintroduced as a colloid system, such as a suspension in an appropriatesolvent phase. To make the suspension, the drug can be dispersed in thesolvent phase using conventional techniques used in colloid chemistry.Depending on a variety of factors, e.g., the nature of the drug, thosehaving ordinary skill in the art can select the solvent to form thesolvent phase of the suspension, as well as the quantity of the drug tobe dispersed in the solvent phase. The suspension can be mixed with apolymer solution and the mixture can be applied on the stent asdescribed above. Alternatively, the drug suspension can be applied onthe stent without being mixed with the polymer solution.

The drug-polymer layer can be applied directly onto at least a part ofthe stent surface to serve as a reservoir for at least one active agentor a drug which is incorporated into the reservoir layer. The optionalprimer layer can be applied between the stent and the reservoir toimprove the adhesion of the drug-polymer layer to the stent. Theoptional topcoat layer can be applied over at least a portion of thereservoir layer and to serve as a rate limiting membrane which helps tocontrol the rate of release of the drug. The topcoat layer can beessentially free from any active agents or drugs.

In one embodiment, any or all of the layers of the stent coating, can bemade of a polymer that is both biologically beneficial and biologicallydegradable, erodable, absorbable, and/or resorbable. In anotherembodiment, just the outermost layer of the coating can be limited tosuch a polymer.

To illustrate in more detail, in the stent coating having all threelayers described above (i.e., the primer, the reservoir layer, and thetopcoat layer), the outermost layer is the topcoat layer, which is madeof a biologically absorbable block copolymer. In this case, optionally,the remaining layers (i.e., the primer and the reservoir layer) can bealso fabricated of a biologically absorbable block copolymer; the blockcopolymer can be the same or different in each layer. If the topcoatlayer is not used, the stent coating can have only two layers: theoptional primer and the reservoir. The reservoir in this case is theoutermost layer of the stent coating and is made of a biologicallyabsorbable block copolymer. Optionally, the primer can be alsofabricated of a biologically absorbable block copolymer, which can bethe same or different in the reservoir and in the primer. In oneembodiment, the biologically absorbable copolymers that can be used formaking any of the stent coating layers include poly(ester amides) (PEA).Optionally, in some other embodiments, condensation copolymers, such aspoly(esters) having no amide bonds, can be used instead of PEAs.

The synthetic techniques that can be used for obtaining both the PEAsand the poly(esters) are described below in the application. Generally,the PEAs are products of reaction between at least one reagent fromgroup A, at least one reagent from group B and a reagent C₁ from groupC. The poly(esters) are products of reaction between at least onereagent from group A and a reagent C₂ from group C. Theprecursor-reagents from groups A, B, and C that can be used arecharacterized as follows.

A. Group A Reagents.

The group A precursor-reagents (hereinafter, “reagents”) that can beused for synthesizing the biologically absorbable copolymers accordingto embodiments of the present invention are summarized in Table 1. Thedefinition used to describe a chemical family to which each of the groupA reagents belongs is also provided in Table 1.

TABLE 1 Group A Reagents No. Code Reagent General Formula ReagentDefinition 1 A₁

Diol-diamine 2 A₂

Amidediol 3 A₃ HO—X—OH Diol 4 A₄ H₂N—Y—NH₂ Diamine

In the general formulae of compounds A₁, A₂, A₃, and A₄ presented inTable 1, the substitutents R₁, R₂, X, and Y can be as follows:

R₁—(a) hydrogen;

(b) methyl (—CH₃);

(c) iso-propyl (-i-C₃H₇);

(d) sec-butyl (-sec-C₄H₉);

(e) iso-butyl (-i-C₄H₉); or

(f) benzyl (—C₆H₅);

R₂—(a) methylene (—CH₂—);

(b) ethylene (—CH₂CH₂—);

(c) methylmethylene [—CH(CH₃)—];

(d) straight chained or branched propylene, such as:

-   -   (d1) n-propylene (—CH₂CH₂CH₂—);    -   (d2) iso-propylene [—CH₂CH(CH₃)—]; or    -   (d3) ethylmethylene [—CH(CH₂CH₃)—];

(e) straight chained or branched butylene, such as:

-   -   (e1) n-butylene (—CH₂CH₂CH₂CH₂—),    -   (e2) iso-butylene [—CH₂CH(CH₃)CH₂—], or    -   (e3) sec-butylene [—CH(CH₂CH₃)CH₂—];

(f) straight chained or branched pentylene, such as:

-   -   (f1) n-pentylene (—CH₂CH₂CH₂CH₂CH₂—),    -   (f2) iso-pentylene [—C(CH₃)₂CH₂CH₂—],    -   (f3) neopentylene {—CH[C(CH₃)₃]—},    -   (f4) 2-methyl-1-butylene [—C(CH₃)(CH₂CH₃)CH₂—],    -   (f5) sec-iso-pentylene [—C(CH₃)₂CH(CH₃)—], or    -   (f6) methylpropylmethylene [—C(CH₃)(CH₂CH₂CH₃)—]; or

(g) groups that are present in some amino acids, such as:

-   -   (g1) methyleneamide (present in asparagine) [—CH₂(CONH₂)—];    -   (g2) ethyleneamide (present in glutamine) [—CH₂CH₂(CONH₂)—];    -   (g3) methylmercaptomethylmethylene (present in methionine)        [—CH₂(CH₂SCH₃)—]; or    -   (g4) n-propyleneamino group (—CH₂CH₂CH₂NH—) which is derived        from 2-pyrrolidine group present (present in proline);

X—straight chained or branched aliphatic alkylene group C_(n)H_(2n),wherein n is an integer between 2 and 16, e.g., methylene, ethylene,propylene, butylene, amylene (pentylene), hexylene, heptylene, octylene,nonylene, decylene, undecylene, or dodecylene group; and

Y—straight chained or branched aliphatic alkylene group C₂H₄ (ethylene),C₃H₆ (propylene), C₄H₈ (butylene), or C₅H₁₀ (pentylene also known asamylene).

The reagent A₁ is a diol-diamine that can be synthesized by condensationof two molar equivalents of an amino acid and one molar equivalent of adiol. The synthesis can be carried under the conditions favoringesterification of the amino acid via the amino acid's carboxyl group.The reaction can be conducted under dehydrating conditions which includeanhydrous environment and an elevated temperature, for example, about50° C., and can be catalyzed by a strong acid or base, e.g.,p-toluenesulfonic acid.

The diol that can be used to make the reagent A₁ has the formulaHO—X—OH, where X is as defined above. Representative examples of diolsthat can be used include ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol,1,9-nonanediol, 1,10-decanediol, 1,11-undecanediol, and1,12-dodecanediol. The amino acid that can be used to make the reagentA₁ has the formula H₂N—CHR₁—COOH, where R₁ is as defined above. Someamino acids that can be used are summarized in Table 2.

TABLE 2 Amino Acids That Can Be Used for Making the Reagent A₁ AminoAcid (H₂N—CHR₁—COOH) No. R₁ Formula Name 1 —H H₂N—CH₂—COOH glycine 2—CH₃

alanine 3 —i-C₃H₇

valine 4 —sec-C₄H₉

isoleucine 5 —i-C₄H₉

leucine 6 C₆H₅CH₂—

phenyl alanine 7 —CH₂)₂—S—CH₃

methionine (α-amino-γ- methylmercaptobutyric acid) 8 —CH₂—C(O)—NH₂

asparagine (α-amino- succinamic acid) 9 —(CH₂)₂—C(O)—NH₂

glutamine (2-amino- glutaramic acid)

In addition to amino acids listed in Table 2, alternatively other aminoacids can be used. One example of such alternative amino acids isproline (2-pyrrolidine carboxylic acid). Other alternative amino acidsthat can be used include some amino acids having free hydroxyl groups orsecond carboxyl groups if the free hydroxyl groups or the secondcarboxyl groups are protected first. The protection is needed so as toavoid interference when reagent A₁ is subsequently reacted with reagentsof groups B and C, as discussed above. Examples of the amino acids thatcan be used after the free hydroxyl or second carboxyl groups areprotected include tyrosine, serine, or glutamic acid.

The reagent A₂ is an amidediol that can be synthesized by condensationof two molar equivalents of a hydroxy acid and one molar equivalent of adiamine. The synthesis can be carried under the conditions favoringformation of an amide bond. The reaction can be conducted underdehydrating conditions, which include anhydrous environment and can becatalyzed by a strong base. Simple heating of the neat startingmaterials with the simultaneous removal of generated water bydistillation can also be used.

The diamine that can be used to make the reagent A₂ has the formulaH₂N—Y—NH₂,

where Y is as defined above. Accordingly, examples of diamines that canbe used include 1,4-butanediamine (putrescine) (Y═CH₂CH₂CH₂CH₂).Alternatively, other diamines, such as 1,2-ethanediamine (Y═CH₂CH₂) or1,5-pentanediamine (cadavarene) (Y═CH₂CH₂CH₂CH₂CH₂) can be used. Thehydroxy acid that can be used to make the reagent A₂ has the formulaHO—R₂—COOH, where R₂ is as defined above. Some hydroxy acids that can beused are summarized in Table 3.

TABLE 3 Hydroxy Acids That Can Be Used For Making The Reagent A₂ HydroxyAcid (HO—R₂—COOH) No. R₂ Formula Name 1 —CH₂— HO—CH₂—COOH glycolic(hydroxyacetic) acid 2 —CH₂—CH₂— HO—CH₂—CH₂—COOH β-hydroxypropionic acid3

lactic (α- hydroxypropionic) acid 4

β-hydroxybutyric acid 5

α-hydroxyvaleric acid 6

β-hydroxyvaleric acid 7 —(CH₂)₅— HO—(CH₂)₅—COOH ε-hydroxycaproic acid 8

α-hydroxycaproic acid 8

β-hydroxycaproic acid 9

δ-hydroxycaproic aid

The reagent A₃ is a common simple diol having the formula HO—X—OH, whereX is as defined above; and the reagent A₄ is a common simple diaminehaving the formula H₂N—Y—NH₂, where Y is as defined above.

B. Group B Reagents.

The group B reagents that can be used for synthesizing the biologicallyabsorbable copolymers according to embodiments of the present inventionare summarized in Table 4. Exemplary definitions used to describe achemical family to which each of the group B reagents belongs is alsoprovided in Table 4.

TABLE 4 Group B Reagents Exemplary Reagent No. Code Reagent GeneralFormula Definition (R₄ = PEG) 1 B₁

PEG-diester-diamine 2 B₂

PEG-amidediol 3 B₃ HO—R₄—OH PEG-diol 4 B₄ H₂N—R₄—NH₂ PEG-diamine

In general formulae of compounds B₁, B₂, B₃, and B₄ presented in Table4, the substitutents R₁ and R₂ are as defined above. One example of theR₄ moiety that can be used is a moiety derived from poly(ethyleneglycol) (PEG). Alternatively, other biologically beneficial moieties canbe used as R₄, for example, moieties derived from poly(propylene glycol)(PPG), random or block copolymers of PEG and PPG, hyaluronic acid,poly(2-hydroxyethylmethacrylate), poly(3-hydroxypropylmethacrylamide),or cellulosics.

The reagent B₁ can be a PEG-diester-diamine moiety (i.e., when R₄=PEG)that can be synthesized by condensation of two molar equivalents of anamino acid and one molar equivalent of PEG. The synthesis can be carriedunder the conditions favoring esterification of the amino acid via thecarboxyl group. The reaction can be conducted under dehydratingconditions which include anhydrous environment and an elevatedtemperature, for example, about 50° C., and can be catalyzed by a strongacid or base, e.g., p-toluenesulfonic acid. To make the reagent B₁, PEGhaving molecular weight between about 100 and 4,000 Daltons, forexample, about 300 Daltons, can be used. Any amino acid listed in Table2 can be used. Alternatively, other amino acids can be used, forexample, tyrosine, serine, or glutamic acid, if free hydroxyl groups oftyrosine and serine or the second carboxyl group of glutamic acid areprotected so as not to interfere when reagent B₁ is subsequently reactedwith reagents of groups A and C, as discussed above.

The reagent B₂ can be a PEG-amidediol that can be synthesized bycondensation of two molar equivalents of a hydroxy acid and one molarequivalent of a PEG-diamine. The synthesis can be carried under theconditions favoring formation of an amide bond. The reaction can beconducted under dehydrating conditions which include anhydrousenvironment, and can be catalyzed by a strong base, or prepared fromneat reagents by heating at high temperature with the simultaneousremoval of generated water, e.g., the removal of water by distillation.Any hydroxy acid listed in Table 3 can be used. PEG terminated withamino groups on both ends (PEG-diamine reagent B₄) can be obtained fromHuntsman Chemical Co. of Houston, Tex. under the trade name JEFFAMINE.

C. Group C Reagents.

The group C reagents that can be used for synthesizing the biologicallyabsorbable copolymers according to embodiments of the present inventionare summarized in Table 5. The definition used to describe a chemicalfamily to which each of the group C reagents belongs is also provided inTable 5.

TABLE 5 Group C Reagents No. Code Reagent General Formula ReagentDefinition 1 C₁

Dicarboxylic acid 2 C₂

PEG-dicarboxylic acid

In general formula of compound C₁ presented in Table 5, the substituentR₃ is simply a covalent bond, or a straight chained or branchedaliphatic alkylene group C_(n)H_(2n), wherein n is an integer having avalue between 0 and 12, e.g. a single bond (n=0), methylene, ethylene,propylene, butylene, amylene (pentylene), hexylene, heptylene, octylene,nonylene, decylene, undecylene, or dodecylene group, or an aromaticgroup, e.g., phenyl or para-phenylene. Some examples of dicarboxylicacids that can be used as the reagent C₁ are summarized in Table 6.

TABLE 6 Dicarboxylic Acids That Can Be Used As The Reagent C₁Dicarboxylic Acid (HOOC—R₃—COOH) No. R₃ Formula Name 1 —(CH₂)₂—HOOC—(CH₂)₂—COOH succinic (butanedioic) acid 2 —(CH₂)₄— HOOC—(CH₂)₄—COOHadipic (hexanedioic) acid 3 —(CH₂)₈— HOOC—(CH₂)₈—COOH sebacic(decanedioic) acid 4 (p)-C₆H₄— HOOC-(p)C₆H₄—COOH terephthalic (1,4-benzene dicarboxylic) acid

In addition to the dicarboxylic acids listed in Table 6, examples ofother dicarboxylic acids that can be also used include oxalic acid,malonic acid, glutaric acid, pimelic acid, suberic acid, or azelaicacid. As mentioned above, to synthesize the PEAs, at least one reagentof group A can be reacted with at least one reagent of group B andreagent C₁. To make the poly(esters), at least one reagent of group Acan be reacted with reagent C₂.

One of several routes can be utilized to synthesize the polymers of thisinvention. Those having ordinary skill in the art can appreciate thatthe reagents of groups A, B, and C may themselves contain hydrolysablebonds, i.e. ester or amide bonds. These reagents can be thenpolymerized, the polymerization creating additional bonds that may beboth ester and amide bonds, only amide bonds, or only ester bonds. Giventhat the reagents can be obtained separately, the types of polymersformed during the polymerization can belong to one of the following fourcategories (A), (B), (C), or (D):

(A) Polymers in which amide bonds are formed between reagents whichthemselves contain ester bonds. Using the reagent codes defined earlier,these polymers can be described as products of reaction between:

-   -   (1) A₁, B₁ and C₁ (A₁-B₁-C₁);    -   (2) A₁, B₄ and C₁ (A₁-B₄-C₁);    -   (3) A₄, B₁ and C₁ (A₄-B₁-C₁); and    -   (4) A₁ and C₂ (A₁-C₂).

(B) Polymers in which amide bonds are formed between reagents whichthemselves contain neither ester nor amide bonds. Using the reagentcodes defined earlier, these polymers can be described as products ofreaction between:

-   -   (1) A₄, B₄ and C₁ (A₄-B₄-C₁); and    -   (2) A₄ and C₂ (A₄-C₂).

(C) Polymers in which both ester and amide bonds are formed between thereagents. The subunits themselves may contain ester and amide bonds,only ester bonds, only amide bonds, or neither ester nor amide bonds.Using the reagent codes defined earlier, these polymers can be describedas products of reaction between:

-   -   (1) A₁, B₂ and C₁ (A₁-B₂-C₁);    -   (2) A₁, B₃ and C₁ (A₁-B₃-C₁);    -   (3) A₂, B₁ and C₁ (A₂-B₁-C₁);    -   (4) A₂, B₄ and C₁ (A₂-B₄-C₁);    -   (5) A₃, B₁ and C₁ (A₃-B₁-C₁);    -   (6) A₃, B₄ and C₁ (A₃-B₄-C₁);    -   (7) A₄, B₂ and C₁ (A₄-B₂-C₁); and    -   (8) A₄, B₃ and C₁ (A₄-B₃-C₁).

(D) Polymers in which ester bonds are formed between reagents whichthemselves may contain amide bonds, or neither amide nor ester bonds.Using the reagent codes defined earlier, these polymers can be describedas products of reaction between:

-   -   (1) A₂, B₂ and C₁ (A₂-B₂-C₁);    -   (2) A₂, B₃ and C₁ (A₂-B₃-C₁);    -   (3) A₂ and C₂ (A₂-C₂);    -   (4) A₃, B₂ and C₁ (A₃-B₂-C₁);    -   (5) A₃, B₃ and C₁ (A₃-B₃-C₁); and    -   (6) A₃ and C₂ (A₃-C₂).

Due to the types of bonds being formed, and the types of bonds present,those having ordinary skill in the art will understand that thepolymerization scheme need be adjusted for each category in order toform the desired polymer while not hydrolyzing or degrading the existingbonds in the reagents, or creating uncontrolled, mixed species. Someexamples of the synthesis of particular polymers are provided below inthe “Examples” section of the present application.

As a result of the synthesis, biologically absorbable PEAs having ageneral formula (A) or poly(esters) having a general formula (B) can beobtained:

-[M-P]_(m)-[M-Q]_(n)-  (A)

-[M₁-P]_(p)-  (B)

wherein:

M is a moiety represented by the structure

P is a moiety including

Q is a moiety selected from a group consisting of

M₁ is a moiety represented by the structure

R₁, R₂, R₃, X and Y are substitutents and moieties as defined above;

Z is a moiety that can be derived from a compound selected from a groupconsisting of poly(ethylene glycol)(PEG), polypropylene glycol) (PPG),random or block copolymers of PEG and PPG, hyaluronic acid,poly(2-hydroxyethylmethacrylate), poly(3-hydroxypropyl methacrylamide),poly(styrene sulfonate), poly(vinyl pyrrolidone), and cellulosics; and

m, n, and p are integers where the value of m can be between 5 and1,800, the value of n can be between 1 and 800 and the value of p can bebetween 4 and 1,500.

Any layer of the stent coating can contain any amount of thebiologically absorbable copolymers described above, or a blend of morethan one of such copolymers. If less than 100% of the layer is made ofthe biologically absorbable copolymers, or blends thereof, describedabove, alternative polymers can comprise the balance. Examples of thealternative polymers that can be used include polyacrylates, such aspoly(butyl methacrylate), poly(ethyl methacrylate), and poly(ethylmethacrylate-co-butyl methacrylate), and fluorinated polymers and/orcopolymers, such as poly(vinylidene fluoride) and poly(vinylidenefluoride-co-hexafluoropropene), poly(N-vinyl pyrrolidone),poly(hydroxyvalerate), poly(L-lactic acid), polycaprolactone,poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane, poly(amino acids), cyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), co-poly(ether-esters), polyalkyleneoxalates, polyphosphazenes, biomolecules (such as fibrin, fibrinogen,cellulose, starch, collagen and hyaluronic acid), polyurethanes,silicones, polyesters, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, vinyl halide polymers and copolymers(such as polyvinyl chloride), polyvinyl ethers (such as polyvinyl methylether), polyvinylidene chloride, polyacrylonitrile, polyvinyl ketones,polyvinyl aromatics (such as polystyrene), polyvinyl esters (such aspolyvinyl acetate), copolymers of vinyl monomers with each other andolefins, e.g., poly(ethylene-co-vinyl alcohol) (EVAL), ethylene-methylmethacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins,and ethylene-vinyl acetate copolymers; polyamides (such as Nylon 66 andpolycaprolactam), alkyd resins, polycarbonates, polyoxymethylenes,polyimides, polyethers, epoxy resins, polyurethanes, rayon,rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate,cellulose acetate butyrate, cellophane, cellulose nitrate, cellulosepropionate, cellulose ethers, and carboxymethyl cellulose.

Representative examples of some solvents suitable for making the stentcoatings include N,N-dimethylacetamide (DMAC), N,N-dimethylformamide(DMF), tethrahydrofurane (THF), cyclohexanone, xylene, toluene, acetone,i-propanol, methyl ethyl ketone, propylene glycol monomethyl ether,methyl butyl ketone, ethyl acetate, n-butyl acetate, and dioxane. Somesolvent mixtures can be used as well. Representative examples of themixtures include:

(1) DMAC and methanol (e.g., a 50:50 by mass mixture);

(2) water, i-propanol, and DMAC (e.g., a 10:3:87 by mass mixture);

(3) i-propanol, and DMAC (e.g., 80:20, 50:50, or 20:80 by massmixtures);

(4) acetone and cyclohexanone (e.g., 80:20, 50:50, or 20:80 by massmixtures);

(5) acetone and xylene (e.g. a 50:50 by mass mixture);

(6) acetone, FLUX REMOVER AMS, and xylene (e.g., a 10:50:40 by massmixture); and

(7) 1,1,2-trichloroethane and chloroform (e.g., a 80:20 by massmixture).

FLUX REMOVER AMS is trade name of a solvent manufactured by Tech Spray,Inc. of Amarillo, Tex. comprising about 93.7% of a mixture of3,3-dichloro-1,1,1,2,2-pentafluoropropane and1,3-dichloro-1,1,2,2,3-pentafluoropropane, and the balance of methanol,with trace amounts of nitromethane. Those having ordinary skill in theart will select the solvent or a mixture of solvents suitable for aparticular polymer being dissolved.

The therapeutic substance which can be used in the reservoir layer caninclude any substance capable of exerting a therapeutic or prophylacticeffect for a patient. The therapeutic substance may include smallmolecule substances, peptides, proteins, oligonucleotides, and the like.The therapeutic substance could be designed, for example, to inhibit theactivity of vascular smooth muscle cells. It can be directed atinhibiting abnormal or inappropriate migration and/or proliferation ofsmooth muscle cells to inhibit restenosis.

Examples of therapeutic substances that can be used includeantiproliferative substances such as actinomycin D, or derivatives andanalogs thereof (manufactured by Sigma-Aldrich of Milwaukee, Wis., orCOSMEGEN available from Merck). Synonyms of actinomycin D includedactinomycin, actinomycin IV, actinomycin I₁, actinomycin X₁, andactinomycin C₁. The active agent can also fall under the genus ofantineoplastic, anti-inflammatory, antiplatelet, anticoagulant,antifibrin, antithrombin, antimitotic, antibiotic, antiallergic andantioxidant substances. Examples of such antineoplastics and/orantimitotics include paclitaxel (e.g. TAXOL® by Bristol-Myers SquibbCo., Stamford, Conn.), docetaxel (e.g. Taxotere®, from Aventis S.A.,Frankfurt, Germany) methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin®from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g. Mutamycin®from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of suchantiplatelets, anticoagulants, antifibrin, and antithrombins includesodium heparin, low molecular weight heparins, heparinoids, hirudin,argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as ANGIOMAX (Biogen, Inc., Cambridge, Mass.). Examplesof such cytostatic or antiproliferative agents include angiopeptin,angiotensin converting enzyme inhibitors such as captopril (e.g.Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.),cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co.,Inc., Whitehouse Station, N.J.); calcium channel blockers (such asnifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand nameMevacor® from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonalantibodies (such as those specific for Platelet-Derived Growth Factor(PDGF) receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), andnitric oxide. An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents which may beappropriate include alpha-interferon, genetically engineered epithelialcells, tacrolimus, dexamethasone, and rapamycin and structuralderivatives or functional analogs thereof, such as40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of EVEROLIMUSavailable from Novartis), 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.

The coatings and methods of the present invention have been describedwith reference to a stent, e.g., a balloon expandable or self-expandablestent. The use of the coating is not limited to stents, and the coatingcan also be used with a variety of other medical devices, such asimplantable medical devices. Examples of the implantable medical devicethat can be used in conjunction with the embodiments of this inventioninclude stent-grafts, grafts (e.g., aortic grafts), catheters,guidewires, artificial heart valves, cerebrospinal fluid shunts,pacemaker electrodes, axius coronary shunts and endocardial leads (e.g.,FINELINE and ENDOTAK, available from Guidant Corporation). Theunderlying structure of the device can be of virtually any design. Thedevice can be made of a metallic material or an alloy such as, but notlimited to, cobalt-chromium alloys (e.g., ELGILOY), stainless steel(316L), “MP35N,” “MP20N,” ELASTINITE (Nitinol), tantalum, tantalum-basedalloys, nickel-titanium alloy, platinum, platinum-based alloys such as,e.g., platinum-iridium alloy, iridium, gold, magnesium, titanium,titanium-based alloys, zirconium-based alloys, or combinations thereof.Devices made from bioabsorbable or biostable polymers can also be usedwith the embodiments of the present invention. “MP35N” and “MP20N” aretrade names for alloys of cobalt, nickel, chromium and molybdenumavailable from Standard Press Steel Co. of Jenkintown, Pa. “MP35N”consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum.“MP20N” consists of 50% cobalt, 20% nickel, 20% chromium, and 10%molybdenum.

Medical devices can be also made from the materials of the invention.Moreover, the polymers can be used for a variety of medicalapplications, including particles for drug delivery to embolize bloodvessels. The polymers of the present invention can have a variety ofmedical applications, including the treatment of stenosis, restenosis,and cancer.

3. Examples

The following examples are provided to further illustrate embodiments ofthe present invention.

Example 1

A copolymer having formula (III) can be synthesized and used in practiceof the invention.

The copolymer (III) is a product of copolymerization of reagents A₁, B₁,and C₁. A₁ can be a diol-diamine shown in Table 1 where R₁ is i-C₄H₉ andX is (CH₂)₆. In other words, A₁ can be synthesized by condensation ofleucine with 1,6-hexanediol. B₁ can be a PEG-diester-diamine shown inTable 4 where R₁ is i-C₄H₉ and PEG₃₀₀ symbolizes a moiety derived frompoly(ethylene glycol) having molecular weight of about 300 Daltons. Inother words, B₁ can be synthesized by condensation of leucine withpoly(ethylene glycol) having molecular weight of about 300 Daltons. C₁can be a dicarboxylic acid shown in Table 5 where R₃ is (CH₂)₈ (sebacicacid, which is also shown in Table 6).

To synthesize copolymer (III), about 30.8 ml dry triethylamine (about0.22 mole) in about 55 ml dry solvent N,N′-dimethylacetamide at roomtemperature can be added to a mixture of:

(a) about 36.37 g (about 0.053 mole) di-para-toluenesulfonic acid saltof bis-(L-leucine)-1,6-hexylene diester;

(b) about 39.3 g (about 0.047 mole) di-para-toluenesulphonic acid saltof bis-(L-leucine)-PEG300 diester; and

(c) about 44.4 g (about 0.1 mole) di-para-nitrophenyl sebacinate.

The mixture can be stirred until full dissolution and then thetemperature can be raised to about 80° C. After stirring for about 24hours, the viscous mixture can be cooled to room temperature, dilutedwith about 100 ml ethanol, and precipitated into an excess of water. Theseparated polymer can be thoroughly washed with water, spread thinlyonto a TEFLON pan, and dried at room temperature under vacuum (about 70mm Hg) for about 24 hours.

Example 2

A copolymer having formula (IV) can be synthesized and used in practiceof the invention.

The copolymer (IV) is a product of copolymerization of reagents A₁, B₁,and C₁. A₁ can be a diol-diamine shown in Table 1, where R₁ is CH₃ and Xis (CH₂)₄. In other words, A₁ can be synthesized by condensation ofalanine with 1,4-butanediol. B₁ can be a PEG-diester-diamine shown inTable 4 where R₁ is i-C₄H₉ and PEG₃₀₀ symbolizes a moiety derived frompoly(ethylene glycol) having molecular weight of about 300 Daltons. Inother words, B₁ can be synthesized by condensation of alanine withpoly(ethylene glycol) having molecular weight of about 300 Daltons. C₁can be a dicarboxylic acid shown in Table 5 where R₃ is (CH₂)₂ (succinicacid, which is also shown in Table 6).

To synthesize copolymer (IV), about 30.8 ml dry triethylamine (about0.22 mole), in about 55 ml dry solvent N,N′-dimethylacetamide, at roomtemperature, can be added to a mixture of:

(a) about 30.43 g (about 0.053 mole) di-para-toluenesulfonic acid saltof bis-(L-alanine)-1,4-butylene diester;

(b) about 36.86 g (about 0.047 mole) di-para-toluenesulfonic acid saltof bis-(L-alanine)-PEG300 diester; and

(c) about 36.0 g (about 0.1 mole) di-para-nitrophenyl succinate.

The mixture can be stirred until full dissolution and then thetemperature can be raised to about 80° C. After stirring for about 24hours, the viscous mixture can be cooled to room temperature, dilutedwith about 100 ml ethanol, and precipitated into an excess of water. Theseparated polymer is thoroughly washed with water, spread thinly into aTEFLON pan, and dried at room temperature under vacuum (about 70 mm Hg)for about 24 hours.

Example 3

A copolymer having formula (V) can be synthesized and used in practiceof the invention.

The copolymer (V) is a product of copolymerization of reagents A₁, B₁,and C₁. A₁ can be a diol-diamine shown in Table 1 where R₁ is i-C₄H₉ andX is (CH₂)₄. In other words, A₁ can be synthesized by condensation ofleucine with 1,4-butanediol. B₁ can be a PEG-diester-diamine shown inTable 4 where R₁ is i-C₄H₉ and PEG₃₀₀ symbolizes a moiety derived frompoly(ethylene glycol) having molecular weight of about 300 Daltons. Inother words, B₁ can be synthesized by condensation of leucine withpoly(ethylene glycol) having molecular weight of about 300 Daltons. C₁can be a dicarboxylic acid shown in Table 5 where R₃ is para-C₆H₄(terephthalic acid, which is also shown in Table 6).

The copolymer (V) can be obtained using the same synthetic technique asdescribed in Example 2 for copolymer (IV), except di-para-nitrophenylterephthalate can be used to make the copolymer (V), instead ofdi-para-nitrophenyl succinate. In copolymer (V), the value of n can bebetween about 64 and about 97 and the value of m can be between about 3and about 36, where m+n=100.

Example 4

A copolymer having formula (VI) can be synthesized and used in practiceof the invention.

The copolymer (VI) is a product of copolymerization of reagents A₁, B₂,and C₁. A₁ can be a diol-diamine shown in Table 1 where R₁ is i-C₄H₉ andX is (CH₂)₆. In other words, A₁ can be synthesized by condensation ofleucine with 1,6-hexanediol. B₂ can be a PEG-amidediol shown in Table 4where R₂ is methylmethylene CH(CH₃).

In other words, B₂ can be synthesized by condensation of lactic acidwith PEG-diamine shown as reagent B₄ in Table 4. PEG-diamine can bebased on poly(ethylene glycol) having molecular weight of about 600Daltons, which is symbolized by the abbreviation PEG₆₀₀.

For example, JEFFAMINE ED-600 available from Huntsman Corp. can be used.JEFFAMINE ED-600 is a trade name of O,O′-bis-[(2-aminopropyl)poly(propylene glycol)-block-poly(ethylene glycol)-block-poly(propyleneglycol)], which is a polyether diamine with a polyalkylene oxidebackbone. The molecular weight of JEFFAMINE ED-600 is about 600 Daltons.

C₁ can be a dicarboxylic acid shown in Table 5 where R₃ is (CH₂)₈(sebacic acid, which is also shown in Table 6). In copolymer (VI), thevalue of n can be between about 60 and about 93 and the value of m canbe between about 7 and about 40, where m+n=100.

Example 5

A copolymer having formula (VII) can be synthesized and used in practiceof the invention.

The copolymer (VII) can be synthesized in same way as the copolymer (VI)of Example 4, except instead of a reagent B₂ (e.g., PEG-amidediol),reagent B₄ (e.g., PEG-diamine) shown in Table 4 can be used. Incopolymer (VII), the value of n can be between about 59 and about 96 andthe value of m can be between about 4 and about 41, where m+n=100.

Example 6

A copolymer having formula (VIII) can be synthesized and used inpractice of the invention.

The copolymer (VIII) is a product of copolymerization of reagents A₂,B₁, and C₁. A₂ can be an amidediol shown in Table 1 where R₂ ismethylmethylene CH(CH₃) and Y is (CH₂)₄. In other words, A₂ can besynthesized by condensation of lactic acid with the 1,4-diamino butane(putrescine).

B₁ can be a PEG-diester-diamine shown in Table 4 where R₁ is i-C₄H₉. Inother words, B₁ can be synthesized by condensation of leucine withpoly(ethylene glycol) having molecular weight of about 2,000 Daltons,which is symbolized by the abbreviation PEG₂₀₀₀.

C₁ can be a dicarboxylic acid shown in Table 5 where R₃ is (CH₂)₈(sebacic acid, which is also shown in Table 6). In copolymer (VIII), thevalue of n can be between about 86 and about 99 and the value of m canbe between about 1 and about 14, where m+n=100.

Example 7

A copolymer having formula (IX) can be synthesized and used in practiceof the invention.

The copolymer (IX) can be synthesized in same way as the copolymer(VIII) of Example 6, except instead of a reagent B₁(PEG-diester-diamine), reagent B₂ (PEG-amidediol) shown in Table 4 canbe used, where R₂ is methylmethylene CH(CH₃). In other words, B₂ can besynthesized by condensation of lactic acid with PEG-diamine shown asreagent B₄ in Table 4. PEG-diamine can be based on poly(ethylene glycol)having molecular weight of about 600 Daltons, which is symbolized by theabbreviation PEG₆₀₀. In copolymer (IX), the integer value of n can bebetween about 69 and about 98 and the value of m can be between about 2and about 31, where m+n=100.

Example 8

A copolymer having formula (X) can be synthesized and used in practiceof the invention.

The copolymer (X) can be synthesized in same way as the copolymer (IX)of Example 7, except that a reagent B₃ shown in Table 4, (HO—R₄—OH), forexample, PEG-diol, can be used instead of a reagent B₂ (e.g.,PEG-amidediol). PEG-diol can be based on poly(ethylene glycol) havingmolecular weight of about 300 Daltons, which is symbolized by theabbreviation PEG₃₀₀.

A₂ and B₃ reagents can be combined and reacted first to form an A₂-B₃moiety, followed by adding a C₁ reagent and completing polycondensation.The conditions for the synthesis can be determined by those havingordinary skill in the art. For example, the final step of the reaction(reacting C₁ with the A₂-B₃ moiety) can be conducted in the presence ofa coupling agent such as carbodiimide.

Optionally, instead of a C₁ diacid, a dichloride of the diacid can beused, for instance, sebacyl dichloride. In copolymer (X), the value of ncan be between about 54 and about 96 and the value of m can be betweenabout 4 and about 46, where m+n=100.

Alternative versions of the copolymer (X) can be also synthesized tomake the copolymer (X) harder. For example, an amino acid with shorterR₂ group or a shorter chain diamine (e.g., ethanediamine instead of1,4-butanediamine) can be used for preparing the reagent A₂.

Other possible methods of increasing the hardness of the copolymer (X)include using a shorter dicarboxylic acid C₁ (e.g., adipic acid insteadof sebacic acid), or using PEG with lower molecular weight, or reducingthe proportion of the PEG-containing units in the overall copolymer (X).

Example 9

A copolymer having formula (XI) can be synthesized and used in practiceof the invention.

The copolymer (XI) can be synthesized in same way as the copolymer (X)of Example 9, except that a reagent B₄ (such as PEG-diamine) shown inTable 4 can be used instead of a reagent B₃ (e.g., PEG-diol).PEG-diamine can be based on poly(ethylene glycol) having molecularweight of about 600 Daltons, which is symbolized by the abbreviationPEG₆₀₀. In copolymer (XI), the value of n can be between about 3 andabout 35, and the value of m can be between about 97 and about 65, wherem+n=100.

Example 10

A copolymer having formula (XII) can be synthesized and used in practiceof the invention.

The copolymer (XII) can be synthesized in same way as the copolymer(VIII) of Example 6, except that a reagent A₃ (diol) shown in Table 1can be used instead of a reagent A₂ (amidediol), where X is (CH₂)₆. Inother words, 1,6-hexanediol can be used as the reagent A₃. Apoly(ethylene glycol) moiety having molecular weight of about 300Daltons can comprise a part of copolymer (XII), which is symbolized bythe abbreviation PEG₃₀₀. In copolymer (XII), the value of n can bebetween about 98 and about 71 and the value of m can be between about 2and about 29, where m+n=100.

Example 11

A copolymer having formula (XIII) can be synthesized and used inpractice of the invention.

The copolymer (XIII) can be synthesized in same way as the copolymer(XII) of Example 10, except that a reagent B₂ (e.g., PEG-amidediol)shown in Table 4 can be used instead of a reagent B₁ (such asPEG-diester-diamine), where R₂ is methylmethylene CH(CH₃). In otherwords, B₂ can be synthesized by condensation of lactic acid withPEG-diamine shown as reagent B₄ in Table 4. PEG-diamine can be based onpoly(ethylene glycol) having molecular weight of about 600 Daltons,which is symbolized by the abbreviation PEG₆₀₀.

In copolymer (XIII), the value of n can be between about 98 and about 76and the value of m can be between about 2 and about 24, where m+n=100.

Example 12

A copolymer having formula (XIV) can be synthesized and used in practiceof the invention.

The copolymer (XIV) can be synthesized in same way as the copolymer(XIII) of Example 11, except that a reagent B₄ (e.g., PEG-diamine) asshown in Table 4 can be used instead of a reagent B₂ (such asPEG-amidediol). PEG-diamine can be based on poly(ethylene glycol) havingmolecular weight between about 300 and about 2,400 Daltons, for example,about 600 Daltons, which is symbolized by the abbreviation PEG₆₀₀.Reagent A₃ (1,6-hexanediol) and reagent C₁ (sebacic acid) can becombined and reacted first to form an A₃-C₁ moiety, followed by addingreagent B₄ and completing polycondensation. To facilitate the formationof the A₃-C₁ moiety, sebacyl dichloride can be used as the C₁ reagentinstead of sebacic acid. The conditions for the synthesis can bedetermined by those having ordinary skill in the art.

In copolymer (XIV), the value of n can be between about 98 and about 73and the value of m can be between about 2 and about 27, where m+n=100.

Example 13

A copolymer having formula (XV) can be synthesized and used in practiceof the invention.

The copolymer (XV) can be synthesized in same way as the copolymer(VIII) of Example 6, except that a reagent A₄ (diamine) shown in Table 1can be used instead of a reagent A₂ (amidediol), where Y is (CH₂)₄.

In other words, putrescine can be used as the reagent A₄. Apoly(ethylene glycol) moiety having molecular weight between about 300Daltons and about 4,000 Daltons, for example, about 300 Daltons, cancomprise a part of copolymer (XV), which is symbolized by theabbreviation PEG_(3oo).

In copolymer (XV), the value of n can be between about 98 and about 73and the value of m can be between about 2 and about 27, where m+n=100.

Example 14

A copolymer having formula (XVI) can be synthesized and used in practiceof the invention.

The copolymer (XVI) can be synthesized in same way as the copolymer (IX)of Example 7, except that a reagent A₄ (diamine) shown in Table 1 can beused instead of a reagent A₂ (amidediol), where Y is (CH₂)₄. In otherwords, putrescine can be used as the reagent A₄.

A poly(ethylene glycol) moiety having molecular weight between about 300Daltons and about 4,000 Daltons, for example, about 600 Daltons, cancomprise a part of copolymer (XVI), which is symbolized by theabbreviation PEG₆₀₀.

In copolymer (XVI), the value of n can be between about 98 and about 77,and the value of m can be between about 2 and about 23, where m+n=100.

Example 15

A copolymer having formula (XVII) can be synthesized and used inpractice of the invention.

The copolymer (XVII) can be synthesized in same way as the copolymer (X)of Example 8, except that a reagent A₄ (diamine) shown in Table 1 can beused instead of a reagent A₂ (amidediol), where Y is (CH₂)₄. In otherwords, putrescine can be used as the reagent A₄.

A poly(ethylene glycol) moiety having molecular weight between about 300Daltons and about 4,000 Daltons, for example, about 2,000 Daltons cancomprise a part of copolymer (XVII), which is symbolized by theabbreviation PEG₂₀₀₀.

In copolymer (XVII), the value of n can be between about 995 about 910the value of m can be between about 5 and about 90, where m+n=1000.

Example 16

A copolymer having formula (XVIII) can be synthesized and used inpractice of the invention.

To synthesize the copolymer (XVIII), reagents A₁ and C₂, can be combinedin the molar ratio of about 1:1 and copolymerized. The conditions forthe synthesis can be determined by those having ordinary skill in theart. A₁ can be a diol-diamine shown in Table 1, where R₁ is i-C₄H₉ and Xis (CH₂)₆. In other words, A₁ can be synthesized by condensation ofleucine with 1,6-hexanediol. C₂ can be a PEG-dicarboxylic acid shown inTable 5, derived from poly(ethylene glycol) having molecular weight ofabout 1,000 Daltons, which is symbolized by the abbreviation PEG₁₀₀₀. Atotal molecular weight of the copolymer (XVIII) can be between about20,000 Daltons and about 50,000 Daltons. The value of the integer p canbe between about 14 and about 360.

Example 17

A copolymer having formula (XIX) can be synthesized and used in practiceof the invention.

The copolymer (XIX) can be synthesized in same way as the copolymer(XVIII) of Example 16, except that a reagent A₂ (amidediol) shown inTable 1 can be used instead of a reagent A₁ (diol-diamine), where R₂ ismethylmethylene CH(CH₃), and Y is (CH₂)₄. In other words, A₂ can besynthesized by condensation of lactic acid with putrescine. C₂ can be aPEG-dicarboxylic acid shown in Table 5 derived from poly(ethyleneglycol) having molecular weight of about 1,000 Daltons, which issymbolized by the abbreviation PEG₁₀₀₀.

A total molecular weight of the copolymer (XIX) can be between about20,000 Daltons and about 50,000 Daltons. The value of the integer p canbe between about 15 and about 390.

Example 18

Co-poly-{[N,N′-adipoyl-bis-(L-alanine)-1,4-butylenediester]₃₇-[N,N′-adipoyl-bis-(L-alanine)-PEG300 diester]₆₇} havingformula (XX) can be synthesized and used in practice of the invention.This copolymer belongs to category (A), type A₁-B₁-C₁, described above.

To synthesize the copolymer (XX), about 41 ml (about 0.293 mole) drytriethylamine in about 75 ml dry solvent N,N′-dimethylacetamide, at roomtemperature, can be added to a mixture of:

(a) about 28.64 g (about 0.0497 mole) di-para-toluenesulfonic acid saltof bis-(L-alanine)-1,4-butylene diester;

(b) about 65.57 g (about 0.0834 mole) di-para-toluenesulphonic acid saltof bis-(L-alanine)-PEG300 diester; and

(c) about 51.62 g (about 0.1331 mole) di-para-nitrophenyl adipate.

The mixture can be stirred until full dissolution and then thetemperature can be raised to about 80° C. After stirring for about 24hours, the viscous mixture can be cooled to room temperature, dilutedwith about 100 ml ethanol, and precipitated into an excess of water. Theseparated polymer can be thoroughly washed with water, spread thinlyonto a TEFLON pan, and dried at room temperature under vacuum (about 70mm Hg) for about 24 hours.

As amide bonds are formed in the presence of existing ester bonds, mildconditions need to be used, and this will be understood by those havingordinary skill in the art. For example, polymerization techniques usinggood leaving groups such as para-nitrophenol or carboxyl groupsactivated by carbodiimides can be used. In this invention, the range ofstoichiometries can be determined by the desired mass content of PEG.

For example, the final polymer can contain between about 5 mass % andabout 50 mass % of PEG. For copolymer (XX), this corresponds to molarratios of the two blocks of (alanine/butanediol-adipic acid) (A₁-C₁blocks) and (alanine/PEG-adipic acid) (B₁-C₁ blocks) between about 94:6and about 12:88.

Example 19

Co-poly-{[N,N′-sebacyl-1,4-butylene diamide]₈₆-[N,N′-sebacyl-(ED-600)diamide]₁₄} having formula (XXI) can be synthesized and used in practiceof the invention. This copolymer belongs to category (B), type(A₄-B₄-C₁), described above.

In formula (XXI), “ED-600” is an abbreviation symbolizing JEFFAMINEED-600 polymer described above (see Example 4).

To synthesize the copolymer (XXI), about 104 ml (about 0.744 mole) drytriethylamine in about 65 ml dry solvent N,N′-dimethylacetamide, at roomtemperature, can be added to a mixture of:

(a) about 23.38 g (about 0.266 mole) dry 1,4-diaminobutane; and

(b) about 25 g (about 0.0417 mole) dry ED-600.

The mixture can be stirred, under a nitrogen atmosphere at roomtemperature, until full dissolution. The mixture can be cooled in icewater and about 80.75 g (about 0.338 mole) sebacoyl chloride can beadded dropwise with stirring. The solution can be allowed to come toambient temperature with stirring stirred continued overnight. Theviscous mixture can then be precipitated into an excess of water. Theseparated polymer can be thoroughly washed with water, spread thinlyinto a TEFLON pan, and dried at room temperature under vacuum (about 70mm Hg) for about 24 hours.

As only amide bonds are present, without any other hydrolysable groups,harsher synthetic conditions can be used for this category as understoodby those having ordinary skill in the art. For example, acid chloridescan be used. The mass contents of PEG in the final copolymer (XXI) canbe between about 5 mass % and about 50 mass %. For copolymer (XXI), thiscorresponds to molar ratios of the two blocks of diamine-sebacic acid(A₄-C₁ blocks) and ED-600-sebacic acid (B₄-C₁ blocks) of between about97:3 and about 57:43.

Example 20

Co-poly-{[N,N′-succinyl-bis-(L-leucine)-1,3-propylenediester]₈₂-[succinyl-PEG₆₀₀ diester]₁₈} having formula (XXII) can besynthesized and used in practice of the invention. This copolymerbelongs to category (C), type (A₁-B₃-C₁), described above.

To synthesize the copolymer (XXII), about 26.8 g (about 0.227 mole)succinic acid, and about 52.3 g (about 0.454 mole) N-hydroxysuccinimidecan be added to about 100 ml dry N,N′-dimethylformamide at roomtemperature under nitrogen and dissolved with stirring. About 93.67 g(about 0.454 mole) dicyclohexylcarbodiimide (DCC) can be to the mixtureadded, and the mixture can be allowed to stir for about 16 hours at roomtemperature.

The reaction mixture can be filtered through filter paper to remove theurea byproduct, and the solution can be placed into a reaction flask.The following compounds can then be added to the reaction mixture withcontinued stirring:

(a) about 55.9 g (about 0.185 mole) the free base ofbis-(L-leucine)-1,3-propylene diester; and

(b) about 25 g (about 0.0417 mole) poly(ethylene glycol) havingmolecular weight of about 600 Daltons (PEG600).

The mixture can be stirred at room temperature for about 2 hours andthen the temperature can be increased to about 60° C. and stirred forabout two more hours. The polymer can precipitated by adding thereaction solution dropwise to about 2 liters of ethyl acetate withstirring. The precipitated polymer can be placed as a thin layer into aTEFLON pan and dried at room temperature under vacuum (about 70 mm Hg)for about 24 hours.

In this category, both amide and ester bonds are present in thecopolymer. Accordingly, mild conditions need to be used, as understoodby those having ordinary skill in the art. For example, carboxylategroups activated by carbodiimides can be used or good leaving groupssuch as para-nitro-phenol can be used. The mass contents of PEG in thefinal copolymer (XXII) can be between about 5 mass % and about 50 mass%. For copolymer (XXII), this corresponds to molar ratios of the twoblocks of leucine/propanediol-succinic acid (A₁-C₁ blocks) andPEG-diol-succinic acid (B₃-C₁ blocks) between about 94:6 and about12:88.

Example 21

Co-poly-{[terephthalyl-bis-(D,L-lactate)-1,4-butylenediamide]₈₁-[terphthalyl-bis-(glycolate)-ED600 diamide]₁₉} having formula(XXIII) can be synthesized and used in practice of the invention. Thiscopolymer belongs to category (D), type (A₂-B₂-C₁), described above.

To synthesize the copolymer (XXIII), the following compounds can becombined in a reaction flask equipped with nitrogen atmosphere, vacuumport, and heating mantle:

(a) about 0.12 g (about 3.5×10⁻⁴ moles) titanium tetrabutoxide;

(b) about 41.2 g (about 0.178 mole) bis-(D,L-lactate)-1,4-butylenediamide;

(c) about 29.83 g (about 0.0417 mole) bis-(glycolate)-ED600 diamide,where (ED-600 is as described above; and

(d) about 42.6 g (about 0.219 mole) dimethyl terephthalate.

The flask can be sealed and heated to about 180° C. for about 2 hours.After about 2 hours, the pressure can be reduced to about 0.1 Torr, andthe solution can be maintained at about 180° C. for about two morehours.

In this category, only ester bonds present in the copolymer. Amide bondsmay, or may not, be present in the reagents. Accordingly,transesterification reactions, under dehydrating conditions, in thepresence of the Lewis or Bronsted acid catalysts can be used. Use ofacid chlorides is also a viable synthetic technique, because the onlyhydrolysable bonds that may be present in the reagents are stable amidebonds. The mass contents of PEG in the final copolymer (XXIII) can bebetween about 5 mass % and about 50 mass %. For copolymer (XXIII), thiscorresponds to molar ratios of the two blocks of (A₂-C₁ blocks) (B₂-C₁blocks) between about 97:3 and about 49:51.

Example 22

A first composition can be prepared, the composition including:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester]₇₅-[N,N′-sebacoyl-L-lysine benzyl ester]₂₅};

(b) between about 0.1 mass % and about 2.0 mass %, for example, about0.5 mass % paclitaxel; and

(c) the balance, a solvent blend of ethanol and 1,1,2-trichloroethane,where the mass ratio between ethanol and 1,1,2-trichloroethane can beabout 1:1.

The first composition can be applied onto the surface of bare 12 mmVISION stent (available from Guidant Corporation). Coating can besprayed and dried to form a drug-polymer layer. A spray coater can beused having a 0.014 round nozzle maintained at ambient temperature witha feed pressure of about 2.5 psi (0.17 atm) and an atomization pressureof about 15 psi (1.02 atm). Coating can be applied at about 20 μg perpass. Between the passes the stent can be dried for about 10 seconds ina flowing air stream at about 50° C. About 270 μg of wet coating can beapplied. The stent can be baked at about 50° C. for about one hour,yielding a drug-polymer layer containing about 250 μg of dry coating.

A second composition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % copolymer (XX) described in Example 18; and

(b) the balance, a solvent blend of ethanol and 1,1,2-trichloroethane,where the mass ratio between ethanol and 1,1,2-trichloroethane can beabout 1:1.

The second composition can be applied onto the dry drug-polymer layer toform the topcoat layer. The same spraying technique and equipment can beused for the applying the topcoat layer as described for thedrug-polymer layer. About 120 μg of wet coating can be applied, followedby drying, e.g., baking at about 50° C. for about one hour, yieldingabout 100 μg of a biocompatible topcoat layer.

Example 23

A first composition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % copolymer co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester]₇₅-[N,N′-sebacoyl-L-lysine-4-amino-TEMPO amide]₂₅}; and

(b) the balance, 100% ethanol.

The first composition can be applied onto the surface of bare 12 mmVISION stent using equipment and coating technique described in Example22. About 120 μg of wet coating can be applied. The stents can be bakedat about 50° C. for about one hour, yielding about 100 μg of a dryprimer layer. The copolymer forming the primer layer includes4-amino-TEMPO (4-amino-2,2′,6,6′-tetramethylpiperidine-1-oxy) moietyattached to lysine via an amide linkage.

A second composition can be prepared by mixing the following components:

(a) between about 0.1 mass % and about 3.0 mass %, for example, about2.0 mass % EVEROLIMUS; and

(b) the balance, 100% ethanol.

The second composition can be applied onto the dry primer layer, to formthe pure drug layer. The same spraying technique and equipment can beused for the applying the drug layer as described above. Coating can beapplied at about 20 μg per pass. Between the passes the stent can bedried for about 10 seconds in a flowing air stream at about 50° C. About110 μg of neat drug coating can be applied. The stent can be baked atabout 50° C. for about one hour, yielding a pure dry drug-layercontaining about 100 μg of dry coating.

A third composition can be prepared by mixing the following components:

(a) between about 0.5 mass % and about 10 mass %, for example, about 1.0mass copolymer (XX) described in Example 18;

(b) between about 0.5 mass % and about 10 mass %, for example, about 1.0mass % co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester]₇₅-[N,N′-sebacoyl-L-lysine benzyl ester]₂₅} described in Example22; and

(c) the balance, 100% ethanol.

The third composition can be applied onto the dry pure drug layer toform the topcoat layer. The same spraying technique and equipment can beused for the applying the topcoat layer as described above. About 440 μgof wet coating can be applied, followed by drying, e.g., baking at about50° C. for about one hour, yielding about 400 μg of a biocompatibletopcoat layer, which can also control the release of the drug.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A medical article comprising an implantable substrate having acoating, the coating including a polymeric product of a reaction betweena first reagent, a second reagent, and a third reagent, wherein: (a) thefirst reagent is selected from a group consisting of compounds havingformulae (1), (2), (3), and (4):

(b) the second reagent is selected from a group consisting of compoundshaving formulae (5), (6), (7), and (8):

(c) the third reagent is a dicarboxylic acid having the formula (9):

wherein: R₁ is hydrogen, methyl, iso-propyl, sec-butyl; iso-butyl, orbenzyl group; R₂ is methylene, methylmethylene, n-propylene,iso-propylene, ethylmethylene, n-butylene, iso-butylene, sec-butylene,or n-amylene group; R₃ is a straight chained or branched aliphaticalkylene group C_(n)H_(2n), wherein n is an integer between 2 and 12; R₄is a moiety derived from a compound selected from a group consisting ofpoly(propylene glycol), random poly(ethylene glycol-co-propyleneglycol), poly(ethylene glycol)-block-poly(propylene glycol), hyaluronicacid, poly(2-hydroxyethyl methacrylate),poly(3-hydroxypropylmethacrylamide), poly(styrene sulfonate), poly(vinylpyrrolidone), and cellulosics; X is a straight chained or branchedaliphatic alkylene group C_(n)H_(2n), wherein n is an integer between 2and 12; and Y is a straight chained or branched aliphatic alkylene groupC_(n)H_(2n), wherein n is 1, 2, or
 5. 2. The medical article of claim 1,wherein the implantable substrate is a stent.
 3. The medical article ofclaim 1, wherein the compound of formula (1) is a diol-diamine, thediol-diamine is a product of condensation of an amino acid and a diol.4. The medical article of claim 3, wherein the amino acid has theformula (10):H₂N—CHR₁—COOH.  (10)
 5. The medical article of claim 3, wherein theamino acid is selected from a group consisting of glycine, alanine,valine, isoleucine, leucine, and phenyl alanine.
 6. The medical articleof claim 3, wherein a diol is selected from a group consisting ofethylene glycol, 1,3-propanediol, 1,4-butane diol, 1,5-pentanediol,1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol,1,10-decanediol, 1,11-undecanediol, and 1,12-dodecanediol.
 7. Themedical article of claim 1, wherein the compound of formula (2) is anamidediol, the amidediol is a product of condensation of a hydroxy acidand a diamine.
 8. The medical article of claim 7, wherein the hydroxyacid has the formula (11):HO—R₂—COOH.  (11)
 9. The medical article of claim 7, wherein the hydroxyacid is selected from a group consisting of glycolic acid, lactic acid,β-hydroxybutyric acid, α-hydroxyvaleric acid, and ε-hydroxycaproic acid.10. The medical article of claim 7, wherein the diamine is selected froma group consisting of putrescine, 1,2-ethanediamine, and cadavarene. 11.The medical article of claim 1, wherein the compound of formula (3) isselected from a group consisting of ethylene glycol, 1,3-propanediol,1,4-butane diol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol,1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,11-undecanediol, and1,12-dodecanediol.
 12. The medical article of claim 1, wherein thecompound of formula (4) is selected from a group consisting ofputrescine, 1,2-ethanediamine, and cadavarene. 13-18. (canceled)
 19. Amedical article comprising an implantable substrate having a coating,the coating including a copolymer having a general formula (12) or (13):-[M-P]_(m)-[M-Q]_(n)-  (12)-[M₁-P]_(p)-  (13) wherein: M is a moiety represented by the structurehaving the formula (14)

P is a moiety selected from a group consisting of structures having theformulae (15), (16), (17), and (18):

Q is a moiety selected from a group consisting of structures having theformulae (19), (20), and (21)

M₁ is a moiety represented by the structure having the formula (22):

R₁ is hydrogen, methyl, iso-propyl, sec-butyl; iso-butyl, or benzylgroup; R₂ is methylene, methylmethylene, n-propylene, iso-propylene,ethylmethylene, n-butylene, iso-butylene, sec-butylene, or n-amylenegroup; R₃ is a straight chained or branched aliphatic alkylene groupC_(n)H_(2n), wherein n is an integer between 2 and 12; X is a straightchained or branched aliphatic alkylene group C_(n)H_(2n), wherein n isan integer between 2 and 12; Y is a straight chained or branchedaliphatic alkylene group C_(n)H_(2n), wherein n is 1, 2, or 5; Z is amoiety derived from a compound selected from a group consisting ofpoly(propylene glycol), random poly(ethylene glycol-co-propyleneglycol), poly(ethylene glycol)-block-poly(propylene glycol), hyaluronicacid, poly(2-hydroxyethyl methacrylate),poly(3-hydroxypropylmethacrylamide), poly(styrene sulfonate), poly(vinylpyrrolidone, and cellulosics; and m, n, and p are integers where thevalue of m is between 5 and 1,800, the value of n is between 1 and 800and the value of p is between 4 and 1,500.
 20. (canceled)
 21. A methodfor fabricating a medical article, the method including synthesizing acopolymer and forming a coating based on the copolymer on at least aportion of an implantable substrate, the synthesizing of the copolymerincluding reacting a first reagent with a second reagent and with athird reagent, wherein: (a) the first reagent is selected from a groupconsisting of compounds having formulae (1), (2), (3), and (4):

(b) the second reagent is selected from a group consisting of compoundshaving formulae (5), (6), (7), and (8):

(c) the third reagent is a dicarboxylic acid having the formula (9):

wherein: R₁ is hydrogen, methyl, iso-propyl, sec-butyl; iso-butyl, orbenzyl group; R₂ is methylene, methylmethylene, n-propylene,iso-propylene, ethylmethylene, n-butylene, iso-butylene, sec-butylene,or n-amylene group; R₃ is a straight chained or branched aliphaticalkylene group C_(n)H_(2n), wherein n is an integer between 2 and 12; R₄is a moiety derived from a compound selected from a group consisting ofpoly(propylene glycol), random poly(ethylene glycol-co-propyleneglycol), poly(ethylene glycol)-block-poly(propylene glycol), hyaluronicacid, poly(2-hydroxyethyl methacrylate),poly(3-hydroxypropylmethacrylamide), poly(styrene sulfonate), poly(vinylpyrrolidone), and cellulosics; X is a straight chained or branchedaliphatic alkylene group C_(n)H_(2n), wherein n is an integer between 2and 12; Y is a straight chained or branched aliphatic alkylene groupC_(n)H_(2n), wherein n is 1, 2, or
 5. 22. The method of claim 21,wherein the implantable substrate is a stent.
 23. The method of claim21, wherein the molar ratio between the first reagent, the secondreagent, and the third reagent is about 1:1:2.
 24. The method of claim21, wherein the compound of formula (1) is a diol-diamine, thediol-diamine is a product of condensation of an amino acid and a diol.25. The method of claim 24, wherein the amino acid has the formula (10):H₂N—CHR₁—COOH.  (10)
 26. The method of claim 24, wherein the amino acidis selected from a group consisting of glycine, alanine, valine,isoleucine, leucine, and phenyl alanine.
 27. The method of claim 24,wherein a diol is selected from a group consisting of ethylene glycol,1,3-propanediol, 1,4-butane diol, 1,5-pentanediol, 1,6-hexanediol,1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol,1,11-undecanediol, and 1,12-dodecanediol.
 28. The method of claim 21,wherein the compound of formula (2) is an amidediol, the amidediol is aproduct of condensation of a hydroxy acid and a diamine.
 29. The methodof claim 28, wherein the hydroxy acid has the formula (11):HO—R₂—COOH.  (11)
 30. The method of claim 28, wherein the hydroxy acidis selected from a group consisting of glycolic acid, lactic acid,β-hydroxybutyric acid, α-hydroxyvaleric acid, and ε-hydroxycaproic acid.31. The method of claim 28, wherein the diamine is selected from a groupconsisting of putrescine, 1,2-ethanediamine, and cadavarene.
 32. Themethod of claim 21, wherein the compound of formula (3) is selected froma group consisting of ethylene glycol, 1,3-propanediol, 1,4-butane diol,1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol,1,9-nonanediol, 1,10-decanediol, 1,11-undecanediol, and1,12-dodecanediol.
 33. The method of claim 21, wherein the compound offormula (4) is selected from a group consisting of putrescine,1,2-ethanediamine, and cadavarene. 34-39. (canceled)
 40. A method forfabricating a medical article, the method including synthesizing acopolymer and forming a coating based on the copolymer on at least aportion of an implantable substrate, wherein the copolymer has a generalformula (12) or (13):-[M-P]_(m)-[M-Q]_(n)-  (12)-[M₁-P]_(p)-  (13) wherein: M is a moiety represented by the structurehaving the formula (14)

P is a moiety selected from a group consisting of structures having theformulae (15), (16), (17), and (18):

Q is a moiety selected from a group consisting of structures having theformulae (19), (20), and (21)

M₁ is a moiety represented by the structure having the formula (22):

R₁ is hydrogen, methyl, iso-propyl, sec-butyl; iso-butyl, or benzylgroup; R₂ is methylene, methylmethylene, n-propylene, iso-propylene,ethylmethylene, n-butylene, iso-butylene, sec-butylene, or n-amylenegroup; R₃ is a straight chained or branched aliphatic alkylene groupC_(n)H_(2n), wherein n is an integer between 2 and 12; X is a straightchained or branched aliphatic alkylene group C_(n)H_(2n), wherein n isan integer between 2 and 12; Y is a straight chained or branchedaliphatic alkylene group C_(n)H_(2n), wherein n is 1, 2, or 5; and Z isa moiety derived from a compound selected from a group consisting ofpoly(propylene glycol), random poly(ethylene glycol-co-propyleneglycol), poly(ethylene glycol)-block-polypropylene glycol), hyaluronicacid, poly(2-hydroxyethyl methacrylate),poly(3-hydroxypropylmethacrylamide), poly(styrene sulfonate), poly(vinylpyrrolidone, and cellulosics; and m, n, and p are integers where thevalue of m is between 5 and 1,800, the value of n is between 1 and 800and the value of p is between 4 and 1,500.
 41. (canceled)
 42. Themedical article of claim 19, wherein the copolymer is of formula (41):


43. The method of claim 40, wherein the copolymer is of formula (41):


44. A medical article comprising an implantable substrate having acoating, the coating including a copolymer having the formula: